Recently, immunocompromised patients due to infection with, for example, AIDS and patients who have a low immunity due to highly developed medical treatment or due to an increase in old people have been increasing. Unfortunately, these phenomena increase the livelihood of fungal infections typified by opportunistic infection. A great deal of attention in medical fields should be paid to deep-seated fungal infections such as candidiasis and aspergillosis, because these fungal infections often cause serious life-threatening problems to, in particular, patients who have a low immunity. Azole antifungal agents typified by fluconazole have been widely used as a curative medicine for these infections. In recent years, however, the emergence of resistant strains and insufficient basic behavior of the known antifungal agents have been identified. Therefore, the development of a curative medicine that is effective for a wider range of strains and is more powerful is desirable (Iyaku Journal, Vol. 37 (7), PP. 115-119, 2001).
According to a recent tendency in the development of azole antifungal agents, antifungal agents have a more complex molecular structure. In particular, a significant technical challenge is how to effectively achieve a structure that includes an asymmetric carbon bonded to an azole methyl group and an adjoining asymmetric carbon (J. Med. Chem., Vol. 41, PP. 1869-1882, 1998). In terms of industrial production, a stable method for producing an antifungal agent inexpensively has not been established so far.
The known processing technology will now be described.
In order to produce the adjoining asymmetric portion, an α-hydroxyphenyl ketone derivative is generally used as the intermediate and the ketone group is subjected to diastereoselective carbon-increasing epoxidation (Chem. Pharm. Bull., Vol. 41 (6), PP. 1035-1042, 1993). Unfortunately, in terms of industrial production, the known method has the following serious disadvantages: (1) The diastereoselectivity in the method is as low as about 4:1. (2) The yield in the isolation of the desired isomer is low. (3) The isolation and the purification require very complex steps. (4) The method causes racemization under some reaction conditions. In addition, a method for producing the α-hydroxyphenyl ketone derivative also includes complex steps (Bioorg. Med. Chem. Lett., Vol. 1 (7), PP. 349-352, 1991), and requires an expensive reaction reagent such as an asymmetric catalyst (Tetrahedron Letters, Vol. 37 (36), PP. 6531-6534, 1996). Thus, the known method is not a satisfactory method in terms of industrial production. Recently, a new, improved method has been reported in which L-alanine is used as the starting material (U.S. Pat. No. 6,300,522). According to this method, however, the fundamental problem is still not solved, because the method also uses an α-hydroxyphenyl ketone derivative as the intermediate. Therefore, the method is still not a satisfactory method in terms of industrial production.
As described above, despite the demand for the development of a new, more useful azole antifungal agent, in terms of industrial production, a stable method for producing an antifungal agent inexpensively has not been established in the known processing technology, because the azole antifungal agent is an optically active compound having two asymmetric carbons. Accordingly, the prompt development of a new, more effective method is desirable regarding the intermediate compound.